Summary
Patients with metastatic melanoma, but also other solid tumors (e.g., lung or breast cancer), may develop cutaneous metastases in advanced stages. The goal of treatment is to alleviate ...symptoms such as pain, fetor, secretions, or bleeding. Current treatment modalities are based on a multimodal treatment approach. Beside surgery, treatment options such as electrochemotherapy, isolated limb perfusion, radiotherapy, and local administration of cytokines or chemotherapy agents are available. In case of concomitant visceral metastases, this local treatment approach may not affect overall survival, but the palliation of these tumor‐associated symptoms very often improves the quality of life for the patient.
Commonly, in patients with melanoma metastases of an unknown primary tumor (MUP), an extensive search for the primary tumor is carried out. Recently, highly recurrent telomerase reverse transcriptase ...(TERT)-promoter mutations were found in malignant melanomas, which may function as driver mutations of skin cancer. The aim of this study was to test the hypothesis that MUP and mucosal melanomas harbor different prevalences of TERT-promoter mutations. Thirty-nine patients with MUP and 53 patients with mucosal melanomas were retrieved. In total, 152 paraffin samples of 92 patients were analyzed, and in 38 patients, multiple samples were tested. Mutational analysis of the TERT-promoter, BRAF, NRAS, and KIT genes was carried out. In total, 92 patients were eligible for mutational analysis. TERT-promoter mutations were found in 33 patients (35.9%): chr5, 1,295,228 C>T (18 patients); chr5, 1,295,250 C>T (11 patients); chr5, 1,295,228-229 CC>TT (three patients); chr5, 1,295,242-243 CC>TT (one patient). The mutations were significantly more prevalent in MUP 26 (66.7%) than in mucosal melanomas seven patients (13.2%); P<0.001. In MUP, BRAF mutations were found in 46.2% of patients (18 patients) and NRAS mutations in 28.2% of patients (11 patients). In mucosal melanoma, NRAS mutations were found in 18.9% of patients (10), and BRAF and KIT mutations in 7.5% of patients (four patients), respectively. The prevalence of TERT-promoter mutations was associated with the patient's sex 23 (51.1%) men, 10 (21.3%) women; P=0.004. No significant correlation was found between TERT-mutation and patient survival. The TERT-promoter genotype of MUP points toward a cutaneous and not mucosal origin. The significant sex differences merit further attention in having putative therapeutic implications.
Serum S100B and LDH, as well as the status of the sentinel node, have been reported as prognostic markers in melanoma patients. The purpose of this study was to determine the value of serum S-100B ...and LDH in melanoma patients prior to sentinel lymph node dissection (SLND) with respect to the clinical outcome.
Serum S100B and LDH were measured prior to SLND in 259 melanoma patients between 2000 and 2006. Upper institutional limits were 0.12 microg/l for S100B and 240U/l for LDH.
The median follow-up time was 27.1 months. The median S-100B value for SN-negative and SN-positive patients was 0.06 microg/l and 0.05 microg/l, respectively (p=0.291). Similarly for LDH, the values were 171.5 U/l and 166.5 U/l, respectively (p=0.763). Neither of the proposed markers were a statistically significant prognostic parameter for disease-free survival (DFS), distant metastasis-free survival (DMFS) and overall survival (OS).
In the present study neither serum S100B nor LDH prior to SLND were useful in predicting the histopathological status of the sentinel node. None of them correlated with DFS, DMFS or OS.
Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic bone marrow transplantation, and has a major effect on the long-term prognosis. The molecular mechanisms underlying ...cGvHD have been only partially revealed, and molecular targeted therapies have not yet been established for clinical use. We examined the effects of the combined inhibition of the Abelson kinase (c-Abl) and platelet-derived growth factor receptors (PDGFR) in experimental sclerodermatous cGvHD. Treatment using imatinib or nilotinib abolished the aberrant activation of c-Abl and PDGFR and protected against experimental cGvHD. Preventive therapy using imatinib or nilotinib inhibited the development of sclerodermatous cGvHD. Clinical features such as weight loss, alopecia, and skin ulcers, and histologic features with dermal thickening and accumulation of collagen were significantly reduced in mice that received imatinib or nilotinib therapy, but not in mice that received prednisone therapy. Of note, imatinib and nilotinib were also effective for treatment of experimental cGvHD that had already been clinically manifested. In summary, the combined inhibition of c-Abl and PDGFR is effective for prevention and treatment of experimental sclerodermatous cGvHD. Considering the high morbidity associated with cGvHD, the lack of efficient molecular therapies for clinical use, and first positive signals from uncontrolled studies of imatinib, combined inhibition of c-Abl and PDGFR might be a promising future strategy for treatment of sclerodermatous cGvHD.
Aberrant methylation of promoter regions involved in silencing of tumor suppressor genes is a key feature of many human cancers including melanoma. These DNA methylation events occur early in cancer ...development, increase with progression, and may therefore serve as biomarkers for the detection and staging of cancer. In our study, we used an epigenomic reactivation screening approach including Combined Bisulfite Restriction Analyses (COBRA) assays to identify novel methylation markers in late-stage melanoma. Two human xenograft melanoma models have been used to identify genes methylated in cancer and reactivated upon treatment with a histone deacetylase inhibitor. Gene expression analysis and promoter scanning for DNA methylation by COBRA assays and bisulfite sequencing were used to identify candidate genes. The methylation status of the CpG island promoter region of genes related to melanoma pathophysiology in skin, lymph node, and visceral metastatic metastases in 28 patients (samples n=35) were assessed. These methylation markers have been evaluated in melanoma metastasis tissue and in control samples from normal skin. The screening in in-vitro and in-vivo systems for methylated genes in melanoma samples showed 10 candidate genes. Using COBRA assays, we detected a methylation pattern in the promoter region of 10 genes with two genes (BASP1, CDH11), together with the patient's age and the log-S100B-level at biopsy, constructing a descriptor with a trend to correlate with shorter time to death.
At present there is no international consensus on laboratory testing during the follow-up of melanoma patients. We carried out a prospective monitoring study on the usefulness of lactate ...dehydrogenase (LDH) and protein S-100B assessment in high-risk melanoma patients. Ninety-seven patients treated within prospective randomized trials on the adjuvant treatment of melanoma received quarterly clinical visits and blood examinations. During the median observation period of 30 months disease progression was observed in 52 of 97 patients (53.1%). The clinical course of melanoma was correlated to elevated LDH and S-100B serum concentrations. The comparative analysis revealed that (i) neither LDH nor S-100B were indicators of in-transit metastases, (ii) clinically apparent lymph nodes were rarely detected because of elevated S-100B (29.4%) or LDH (11.8%) only, and (iii) the S-100B assessment was superior to LDH in the identification of early distant metastasis (53.8 vs. 23.1%; P=0.008). The rate of false-positive (elevated) LDH-serum levels and S-100B-serum levels in clinically disease-free melanoma patients did not differ significantly (S-100B 1.9% vs. LDH 1.6%). Our data indicate that only protein S-100B might be used as a highly specific and relatively sensitive marker of early distant metastasis. Both markers, LDH and S-100B, are not able to identify loco-regional metastases with a low tumor load in high-risk melanoma patients.
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